Editing Chemotherapy (section)

== Treatment strategies ==
{| class="wikitable" style="float: right;"
|+ Common combination [[chemotherapy regimen]]s<ref name=Corrie />
! scope="col" | Cancer type
! scope="col" | Drugs
! scope="col" | Acronym
|-
! scope="row" rowspan="2" |[[Breast cancer]]
| [[Cyclophosphamide]], [[methotrexate]], [[5-fluorouracil]], [[vinorelbine]]  || CMF
|-
| [[Doxorubicin]], [[cyclophosphamide]]|| AC
|-
! scope="row" rowspan="3" |[[Hodgkin's lymphoma]]
| [[Docetaxel]], [[doxorubicin]], [[cyclophosphamide]]
|TAC
|-
|[[Doxorubicin]], [[bleomycin]], [[vinblastine]], [[dacarbazine]]
|ABVD
|-
|[[Chlormethine|Mustine]], [[vincristine]], [[procarbazine]], [[prednisolone]]
|MOPP
|-
! scope="row" | [[Non-Hodgkin's lymphoma]]
|[[Cyclophosphamide]], [[doxorubicin]], [[vincristine]], [[prednisolone]]|| CHOP, R-CVP
|-
! scope="row" | [[Germ cell tumor]]
|[[Bleomycin]], [[etoposide]], [[cisplatin]]|| BEP
|-
! scope="row" rowspan="2" |[[Stomach cancer]]<ref name=CochraneGastric2017>{{cite journal | vauthors = Wagner AD, Syn NL, Moehler M, Grothe W, Yong WP, Tai BC, Ho J, Unverzagt S | title = Chemotherapy for advanced gastric cancer | journal = The Cochrane Database of Systematic Reviews | volume = 2017 | pages = CD004064 | date = August 2017 | issue = 8 | pmid = 28850174 | pmc = 6483552 | doi = 10.1002/14651858.cd004064.pub4 }}</ref>
| [[Epirubicin]], [[cisplatin]], [[Fluorouracil|5-fluorouracil]]|| ECF
|-
|[[Epirubicin]], [[cisplatin]], [[capecitabine]]|| ECX
|-
! scope="row" | [[Bladder cancer]]
| [[Methotrexate]], [[vincristine]], [[doxorubicin]], [[cisplatin]]|| MVAC
|-
! scope="row" | [[Lung cancer]]
| [[Cyclophosphamide]], [[doxorubicin]], [[vincristine]], [[vinorelbine]]|| CAV
|-
! scope="row" | [[Colorectal cancer]]
| [[5-fluorouracil]], [[folinic acid]], [[oxaliplatin]] || [[FOLFOX]]
|-
! scope="row" | [[Pancreatic cancer]]
| [[Gemcitabine]], [[5-fluorouracil]] || FOLFOX
|-
![[Bone cancer]]
|[[Doxorubicin]], [[cisplatin]], [[methotrexate]], [[ifosfamide]], [[etoposide]]
|MAP/MAPIE
|-
|}

There are a number of strategies in the administration of chemotherapeutic drugs used today. Chemotherapy may be given with a [[cure|curative]] intent or it may aim to prolong life or to [[Palliative care|palliate symptoms]].
* Induction chemotherapy is the first line treatment of cancer with a chemotherapeutic drug. This type of chemotherapy is used for curative intent.<ref name="Resistance to cancer chemotherapy"/><ref name=Airley2009>{{cite book |author=Rachel Airley|title=Cancer chemotherapy |publisher=Wiley-Blackwell|year=2009 |isbn=978-0-470-09254-5}}</ref>{{rp|55–59}}
* Combined modality chemotherapy is the use of drugs with other [[Cancer#Treatments|cancer treatments]], such as [[surgery]], [[radiation therapy]], or [[hyperthermia therapy]].
* Consolidation chemotherapy is given after remission in order to prolong the overall disease-free time and improve overall survival. The drug that is administered is the same as the drug that achieved remission.<ref name=Airley2009/>{{rp|55–59}}
* Intensification chemotherapy is identical to consolidation chemotherapy but a different drug than the induction chemotherapy is used.<ref name=Airley2009/>{{rp|55–59}}
* [[Combination chemotherapy]] involves treating a person with a number of different drugs simultaneously. The drugs differ in their mechanism and side-effects. The biggest advantage is minimising the chances of resistance developing to any one agent. Also, the drugs can often be used at lower doses, reducing toxicity.<ref name=Airley2009/>{{rp|55–59}}<ref name=Wood2005>{{cite book | last1 = Wood | first1 = Miriam | first2 = David | last2 = Brighton | name-list-style = vanc  |title=The Royal Marsden Hospital handbook of cancer chemotherapy: a guide for the multidisciplinary team|publisher=Elsevier Churchill Livingstone|location=St. Louis, Mo |year=2005|isbn=978-0-443-07101-0}}</ref>{{rp|17–18}}<ref name=CochraneGastric2017/>
* [[Neoadjuvant]] chemotherapy is given prior to a local treatment such as surgery, and is designed to shrink the primary tumor.<ref name=Airley2009/>{{rp|55–59}} It is also given for cancers with a high risk of micrometastatic disease.<ref name=Perry2008>{{cite book |author=Perry, Michael J. |title=The Chemotherapy source book |publisher=Wolters Kluwer Health/Lippincott Williams & Wilkins|location=Philadelphia |year=2008|isbn=978-0-7817-7328-7}}</ref>{{rp|42}}
* [[Adjuvant chemotherapy]] is given after a local treatment (radiotherapy or surgery). It can be used when there is little evidence of cancer present, but there is risk of recurrence.<ref name=Airley2009/>{{rp|55–59}} It is also useful in killing any cancerous cells that have spread to other parts of the body. These [[micrometastases]] can be treated with adjuvant chemotherapy and can reduce relapse rates caused by these disseminated cells.<ref name="pmid16061845">{{cite journal | vauthors = Epstein RJ | title = Maintenance therapy to suppress micrometastasis: the new challenge for adjuvant cancer treatment | journal = Clinical Cancer Research | volume = 11 | issue = 15 | pages = 5337–41 | date = August 2005 | pmid = 16061845 | doi = 10.1158/1078-0432.CCR-05-0437 | doi-access = free }}</ref>
* Maintenance chemotherapy is a repeated low-dose treatment to prolong remission.<ref name=CochraneGastric2017/><ref name=Airley2009/>{{rp|55–59}}
* Salvage chemotherapy or palliative chemotherapy is given without curative intent, but simply to decrease tumor load and increase life expectancy. For these regimens, in general, a better toxicity profile is expected.<ref name=Airley2009/>{{rp|55–59}}

All [[chemotherapy regimen]]s require that the recipient be capable of undergoing the treatment. [[Performance status]] is often used as a measure to determine whether a person can receive chemotherapy, or whether dose reduction is required.  Because only a fraction of the cells in a tumor die with each treatment ([[fractional kill]]), repeated doses must be administered to continue to reduce the size of the tumor.<ref name=skeel>{{cite book |name-list-style=vanc |last1=Skeel |first1=R. T. |year=2003 |title=Handbook of Cancer Chemotherapy (paperback) |publisher=Lippincott Williams & Wilkins |edition=6th |isbn=978-0-7817-3629-9 |url-access=registration |url=https://archive.org/details/handbookofcancer00rola }}</ref> Current chemotherapy regimens apply drug treatment in cycles, with the frequency and duration of treatments limited by toxicity.<ref name=chabner>{{cite book | vauthors = Chabner B, Longo DL |year=2005 | edition=4th |title= Cancer Chemotherapy and Biotherapy: Principles and Practice| url = https://archive.org/details/cancerchemothera0000unse_v1m4 | url-access = registration |location= Philadelphia |publisher= Lippincott Willians & Wilkins |isbn= 978-0-7817-5628-0}}</ref>

=== Effectiveness ===
The effectiveness of chemotherapy depends on the type of cancer and the stage. The overall effectiveness ranges from being curative for some cancers, such as some [[leukemias]],<ref>{{cite journal | vauthors = Nastoupil LJ, Rose AC, Flowers CR | title = Diffuse large B-cell lymphoma: current treatment approaches | journal = Oncology | volume = 26 | issue = 5 | pages = 488–95 | date = May 2012 | pmid = 22730604 }}</ref><ref>{{cite journal | vauthors = Freedman A | title = Follicular lymphoma: 2012 update on diagnosis and management | journal = American Journal of Hematology | volume = 87 | issue = 10 | pages = 988–95 | date = October 2012 | pmid = 23001911 | doi = 10.1002/ajh.23313 | s2cid = 35447562 | doi-access = free }}</ref> to being ineffective, such as in some [[brain tumors]],<ref>{{cite journal | vauthors = Rampling R, James A, Papanastassiou V | title = The present and future management of malignant brain tumours: surgery, radiotherapy, chemotherapy | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 75 | issue = Suppl 2 | pages = ii24-30 | date = June 2004 | pmid = 15146036 | pmc = 1765659 | doi = 10.1136/jnnp.2004.040535 }}</ref> to being needless in others, like most [[non-melanoma skin cancer]]s.<ref>{{cite journal | vauthors = Madan V, Lear JT, Szeimies RM | title = Non-melanoma skin cancer | journal = Lancet | volume = 375 | issue = 9715 | pages = 673–85 | date = February 2010 | pmid = 20171403 | doi = 10.1016/S0140-6736(09)61196-X | pmc = 3339125 }}</ref>

=== Dosage ===
[[File:Chemotherapy dose response graph.png|thumb|left|Dose response relationship of cell killing by chemotherapeutic drugs on normal and cancer cells. At high doses the percentage of normal and cancer cells killed is very similar. For this reason, doses are chosen where anti-tumour activity exceeds normal cell death.<ref name=Corrie />]]
Dosage of chemotherapy can be difficult: If the dose is too low, it will be ineffective against the tumor, whereas, at excessive doses, the toxicity ([[adverse effect|side-effects]]) will be intolerable to the person receiving it.<ref name=Corrie /> The standard method of determining chemotherapy dosage is based on calculated [[body surface area]] (BSA). The BSA is usually calculated with a mathematical formula or a [[nomogram]], using the recipient's weight and height, rather than by direct measurement of body area. This formula was originally derived in a 1916 study and attempted to translate medicinal doses established with laboratory animals to equivalent doses for humans.<ref>{{cite journal | vauthors = Du Bois D, Du Bois EF | title = A formula to estimate the approximate surface area if height and weight be known. 1916 | journal = Nutrition | volume = 5 | issue = 5 | pages = 303–11; discussion 312–3 | year = 1989 | pmid = 2520314 }}</ref> The study only included nine human subjects.<ref name="dosing strategies">{{cite journal | vauthors = Felici A, Verweij J, Sparreboom A | title = Dosing strategies for anticancer drugs: the good, the bad and body-surface area | journal = European Journal of Cancer | volume = 38 | issue = 13 | pages = 1677–84 | date = September 2002 | pmid = 12175683 | doi = 10.1016/s0959-8049(02)00151-x }}</ref> When chemotherapy was introduced in the 1950s, the BSA formula was adopted as the official standard for chemotherapy dosing for lack of a better option.<ref name="pmid17305252">{{cite journal | vauthors = Kaestner SA, Sewell GJ | title = Chemotherapy dosing part I: scientific basis for current practice and use of body surface area | journal = Clinical Oncology | volume = 19 | issue = 1 | pages = 23–37 | date = February 2007 | pmid = 17305252 | doi = 10.1016/j.clon.2006.10.010 | hdl = 10026.1/3714 | hdl-access = free }}</ref><ref>{{cite journal | vauthors = Pinkel D | title = The use of body surface area as a criterion of drug dosage in cancer chemotherapy | journal = Cancer Research | volume = 18 | issue = 7 | pages = 853–6 | date = August 1958 | pmid = 13573353 }}</ref>

The validity of this method in calculating uniform doses has been questioned because the formula only takes into account the individual's weight and height. Drug absorption and clearance are influenced by multiple factors, including age, sex, metabolism, disease state, organ function, drug-to-drug interactions, genetics, and obesity, which have major impacts on the actual concentration of the drug in the person's bloodstream.<ref name="pmid17305252" /><ref name="pmid11953888">{{cite journal | vauthors = Gurney H | title = How to calculate the dose of chemotherapy | journal = British Journal of Cancer | volume = 86 | issue = 8 | pages = 1297–302 | date = April 2002 | pmid = 11953888 | pmc = 2375356 | doi = 10.1038/sj.bjc.6600139 }}</ref><ref name="pmid22965963">{{cite journal | vauthors = Beumer JH, Chu E, Salamone SJ | title = Body-surface area-based chemotherapy dosing: appropriate in the 21st century? | journal = Journal of Clinical Oncology | volume = 30 | issue = 31 | pages = 3896–7 | date = November 2012 | pmid = 22965963 | doi = 10.1200/JCO.2012.44.2863 | doi-access = free }}</ref> As a result, there is high variability in the systemic chemotherapy drug concentration in people dosed by BSA, and this variability has been demonstrated to be more than ten-fold for many drugs.<ref name="dosing strategies" /><ref name="role of body">{{cite journal | vauthors = Baker SD, Verweij J, Rowinsky EK, Donehower RC, Schellens JH, Grochow LB, Sparreboom A | title = Role of body surface area in dosing of investigational anticancer agents in adults, 1991-2001 | journal = Journal of the National Cancer Institute | volume = 94 | issue = 24 | pages = 1883–8 | date = December 2002 | pmid = 12488482 | doi = 10.1093/jnci/94.24.1883 | doi-access = free }}</ref> In other words, if two people receive the same dose of a given drug based on BSA, the concentration of that drug in the bloodstream of one person may be 10 times higher or lower compared to that of the other person.<ref name="role of body" /> This variability is typical with many chemotherapy drugs dosed by BSA, and, as shown below, was demonstrated in a study of 14 common chemotherapy drugs.<ref name="dosing strategies" />

[[File:Improvement in Response Rate.jpg|thumb|180px|right|5-FU dose management results in significantly better response and survival rates versus BSA dosing.<ref name="individual fluorouracil" />]]
The result of this pharmacokinetic variability among people is that many people do not receive the right dose to achieve optimal treatment effectiveness with minimized toxic side effects. Some people are overdosed while others are underdosed.<ref name="pmid17305252" /><ref name="pmid11953888" /><ref name="pmid22965963" /><ref name="individual fluorouracil">{{cite journal | vauthors = Gamelin E, Delva R, Jacob J, Merrouche Y, Raoul JL, Pezet D, Dorval E, Piot G, Morel A, Boisdron-Celle M | s2cid = 9557055 | title = Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: results of a multicenter randomized trial of patients with metastatic colorectal cancer | journal = Journal of Clinical Oncology | volume = 26 | issue = 13 | pages = 2099–105 | date = May 2008 | pmid = 18445839 | doi = 10.1200/jco.2007.13.3934 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Saam J, Critchfield GC, Hamilton SA, Roa BB, Wenstrup RJ, Kaldate RR | title = Body surface area-based dosing of 5-fluoruracil results in extensive interindividual variability in 5-fluorouracil exposure in colorectal cancer patients on FOLFOX regimens | journal = Clinical Colorectal Cancer | volume = 10 | issue = 3 | pages = 203–6 | date = September 2011 | pmid = 21855044 | doi = 10.1016/j.clcc.2011.03.015 }}</ref><ref name="dose adjustment">{{cite journal | vauthors = Capitain O, Asevoaia A, Boisdron-Celle M, Poirier AL, Morel A, Gamelin E | title = Individual fluorouracil dose adjustment in FOLFOX based on pharmacokinetic follow-up compared with conventional body-area-surface dosing: a phase II, proof-of-concept study | journal = Clinical Colorectal Cancer | volume = 11 | issue = 4 | pages = 263–7 | date = December 2012 | pmid = 22683364 | doi = 10.1016/j.clcc.2012.05.004 }}</ref><ref>{{cite journal | vauthors = Kaldate RR, Haregewoin A, Grier CE, Hamilton SA, McLeod HL | title = Modeling the 5-fluorouracil area under the curve versus dose relationship to develop a pharmacokinetic dosing algorithm for colorectal cancer patients receiving FOLFOX6 | journal = The Oncologist | volume = 17 | issue = 3 | pages = 296–302 | year = 2012 | pmid = 22382460 | pmc = 3316912 | doi = 10.1634/theoncologist.2011-0357 }}</ref> For example, in a randomized clinical trial, investigators found 85% of metastatic colorectal cancer patients treated with 5-fluorouracil (5-FU) did not receive the optimal therapeutic dose when dosed by the BSA standard—68% were underdosed and 17% were overdosed.<ref name="individual fluorouracil" />

There has been controversy over the use of BSA to calculate chemotherapy doses for people who are [[obese]].<ref name="dosing chemotherapy">{{cite journal | vauthors = Hunter RJ, Navo MA, Thaker PH, Bodurka DC, Wolf JK, Smith JA | title = Dosing chemotherapy in obese patients: actual versus assigned body surface area (BSA) | journal = Cancer Treatment Reviews | volume = 35 | issue = 1 | pages = 69–78 | date = February 2009 | pmid = 18922643 | doi = 10.1016/j.ctrv.2008.07.005 }}</ref> Because of their higher BSA, clinicians often arbitrarily reduce the dose prescribed by the BSA formula for fear of [[overdosing]].<ref name="dosing chemotherapy" /> In many cases, this can result in sub-optimal treatment.<ref name="dosing chemotherapy" />

Several clinical studies have demonstrated that when chemotherapy dosing is individualized to achieve optimal systemic drug exposure, treatment outcomes are improved and toxic side effects are reduced.<ref name="individual fluorouracil" /><ref name="dose adjustment" /> In the 5-FU clinical study cited above, people whose dose was adjusted to achieve a pre-determined target exposure realized an 84% improvement in treatment response rate and a six-month improvement in overall survival (OS) compared with those dosed by BSA.<ref name="individual fluorouracil" />

[[File:Toxicity.png|thumb|180px|left|alt=Toxicity. Diarrhea. BSA-based dose, 18%. Dose-adjusted, 4%. Hematologic. BSA-based dose, 2%. Dose-adjusted, 0%.|5-FU dose management avoids serious side effects experienced with BSA dosing.<ref name="individual fluorouracil" />]]
{{multiple image
| align             = right
| direction         = vertical
| width             = 100
| image1            = Response 1.jpg
| image2            = Survival 1.png
| caption2          = 5-FU dose management in the FOLFOX regimen increases treatment response significantly and improves survival by six months.<ref name="dose adjustment" />
}}
In the same study, investigators compared the incidence of common 5-FU-associated grade 3/4 toxicities between the dose-adjusted people and people dosed per BSA.<ref name="individual fluorouracil" /> The incidence of debilitating grades of diarrhea was reduced from 18% in the BSA-dosed group to 4% in the dose-adjusted group and serious hematologic side effects were eliminated.<ref name="individual fluorouracil" /> Because of the reduced toxicity, dose-adjusted patients were able to be treated for longer periods of time.<ref name="individual fluorouracil" /> BSA-dosed people were treated for a total of 680 months while people in the dose-adjusted group were treated for a total of 791 months.<ref name="individual fluorouracil" /> Completing the course of treatment is an important factor in achieving better treatment outcomes.

Similar results were found in a study involving people with colorectal cancer who have been treated with the popular [[FOLFOX]] regimen.<ref name="dose adjustment" /> The incidence of serious diarrhea was reduced from 12% in the BSA-dosed group of patients to 1.7% in the dose-adjusted group, and the incidence of severe mucositis was reduced from 15% to 0.8%.<ref name="dose adjustment" />

The FOLFOX study also demonstrated an improvement in treatment outcomes.<ref name="dose adjustment" /> Positive response increased from 46% in the BSA-dosed group to 70% in the dose-adjusted group. Median progression free survival (PFS) and overall survival (OS) both improved by six months in the dose adjusted group.<ref name="dose adjustment" />

One approach that can help clinicians individualize chemotherapy dosing is to measure the drug levels in blood plasma over time and adjust dose according to a formula or algorithm to achieve optimal exposure. With an established target exposure for optimized treatment effectiveness with minimized toxicities, dosing can be personalized to achieve target exposure and optimal results for each person. Such an algorithm was used in the clinical trials cited above and resulted in significantly improved treatment outcomes.<ref>{{Cite journal |last1=Canal |first1=P. |last2=Chatelut |first2=E. |last3=Guichard |first3=S. |date=1998 |title=Practical treatment guide for dose individualisation in cancer chemotherapy |url=https://pubmed.ncbi.nlm.nih.gov/9878990/ |journal=Drugs |volume=56 |issue=6 |pages=1019–1038 |doi=10.2165/00003495-199856060-00006 |issn=0012-6667 |pmid=9878990|s2cid=36211632 }}</ref>

Oncologists are already individualizing dosing of some cancer drugs based on exposure. [[Carboplatin]]<ref name=Hanna2008>{{cite book |editor3=Fergus Macbeth |editor1=Hanna, Louise |editor2=Crosby, Tom |title=Practical clinical oncology |publisher=Cambridge University Press |location=Cambridge, UK |year=2008|isbn=978-0-521-61816-8}}</ref>{{rp|4}} and [[busulfan]]<ref>{{cite journal | vauthors = Buffery PJ, Allen KM, Chin PK, Moore GA, Barclay ML, Begg EJ | title = Thirteen years' experience of pharmacokinetic monitoring and dosing of busulfan: can the strategy be improved? | journal = Therapeutic Drug Monitoring | volume = 36 | issue = 1 | pages = 86–92 | date = February 2014 | pmid = 24299921 | doi = 10.1097/FTD.0b013e31829dc940 | s2cid = 28646787 }}</ref><ref>{{cite journal| vauthors = Bartelink IH, Bredius RG, Belitser SV, Suttorp MM, Bierings M, Knibbe CA, Egeler M, Lankester AC, Egberts AC, Zwaveling J, Boelens JJ | display-authors = 6 |title=Association Between Busulfan Exposure and Outcome in Children Receiving Intravenous Busulfan Before Hematopoietic Stem Cell Transplantation|journal=Ther Drug Monit|volume=36|issue=1|pages=93–99| pmid = 24061446 | year = 2014 | doi = 10.1097/FTD.0b013e3182a04fc7 | s2cid = 21072472 }}</ref> dosing rely upon results from blood tests to calculate the optimal dose for each person. Simple blood tests are also available for dose optimization of [[methotrexate]],<ref>{{cite web|url=http://ark-tdm.com/DB_methotrexate.html|title=ARK Methotrexate Assay|publisher=Ark Diagnostics|access-date=28 April 2014|archive-url=https://web.archive.org/web/20140428150337/http://ark-tdm.com/DB_methotrexate.html|archive-date=28 April 2014|url-status=dead}}</ref> 5-FU, [[paclitaxel]], and [[docetaxel]].<ref>{{cite web|url=http://mycaretests.com|title=Customizing Chemotherapy for Better Cancer Care|publisher=My Care Diagnostics|access-date=25 November 2018|archive-url=https://web.archive.org/web/20140428135326/http://www.mycaretests.com/|archive-date=28 April 2014|url-status=dead}}</ref><ref>{{cite web|url=http://bettercancercare.com|title=A Brief History of BSA Dosing|publisher=My Care Diagnostics}}</ref>

The serum albumin level immediately prior to chemotherapy administration is an independent prognostic predictor of survival in various cancer types.<ref>{{cite journal | vauthors = Asher V, Lee J, Bali A | title = Preoperative serum albumin is an independent prognostic predictor of survival in ovarian cancer | journal = Medical Oncology | volume = 29 | issue = 3 | pages = 2005–9 | date = September 2012 | pmid = 21735143 | doi = 10.1007/s12032-011-0019-5 | s2cid = 19558612 }}</ref>

=== Types ===
[[File:Cross-linked DNA by nitrogen mustard.png|thumb|left| Two DNA bases that are cross-linked by a nitrogen mustard. Different nitrogen mustards will have different chemical groups (R). The nitrogen mustards most commonly alkylate the N7 nitrogen of guanine (as shown here) but other atoms can be alkylated.<ref name =Siddik />]]

==== Alkylating agents ====
{{Main|Alkylating antineoplastic agent}}
Alkylating agents are the oldest group of chemotherapeutics in use today. Originally derived from [[mustard gas]] used in [[World War I]], there are now many types of alkylating agents in use.<ref name=Corrie /> They are so named because of their ability to [[alkylation|alkylate]] many molecules, including [[protein]]s, [[RNA]] and [[DNA]]. This ability to bind [[covalent bond|covalently]] to DNA via their [[alkyl group]] is the primary cause for their anti-cancer effects.<ref name=lind>{{cite journal|last1=Lind M.J.|title=Principles of cytotoxic chemotherapy|journal=Medicine|year=2008|volume=36|issue=1|pages=19–23|doi=10.1016/j.mpmed.2007.10.003|first1=M.J.}}</ref> DNA is made of two strands and the molecules may either bind twice to one strand of DNA (intrastrand crosslink) or may bind once to both strands (interstrand crosslink). If the cell tries to replicate crosslinked DNA during [[cell division]], or tries to repair it, the DNA strands can break. This leads to a form of programmed cell death called [[apoptosis]].<ref name =Siddik>{{cite book | vauthors = Siddik ZH |year=2005|publisher=John Wiley & Sons, Ltd|doi=10.1002/0470025077.chap84b|title=The Cancer Handbook|isbn=978-0470025062|chapter=Mechanisms of Action of Cancer Chemotherapeutic Agents: DNA-Interactive Alkylating Agents and Antitumour Platinum-Based Drugs}}</ref><ref name="pmid19002790" /> Alkylating agents will work at any point in the cell cycle and thus are known as cell cycle-independent drugs. For this reason, the effect on the cell is dose dependent; the fraction of cells that die is directly proportional to the dose of drug.<ref name="pmid14508075" />

The subtypes of alkylating agents are the [[nitrogen mustard]]s, [[nitrosoureas]], [[tetrazine]]s, [[aziridines]],<ref>{{cite journal | vauthors = Giorgi-Renault S, Renault J, Baron M, Gebel-Servolles P, Delic J, Cros S, Paoletti C | year = 1988 | title = Heterocyclic quinones XIII. Dimerization in the series of 5,8-quinazolinediones: Synthesis and anti tumor effects of bis(4-amino-5,8-quinazolinediones) | journal = Chem. Pharm. Bull. | volume = 36 | issue = 10| pages = 3933–3947 | doi=10.1248/cpb.36.3933| pmid = 3245973 | doi-access = free }}</ref> [[cisplatin]]s and derivatives, and non-classical alkylating agents. Nitrogen mustards include [[mechlorethamine]], [[cyclophosphamide]], [[melphalan]], [[chlorambucil]], [[ifosfamide]] and [[busulfan]]. Nitrosoureas include [[N-Nitroso-N-methylurea]] (MNU), [[carmustine]] (BCNU), [[lomustine]] (CCNU) and [[semustine]] (MeCCNU), [[fotemustine]] and [[streptozotocin]]. Tetrazines include [[dacarbazine]], [[mitozolomide]] and [[temozolomide]]. Aziridines include [[thiotepa]], [[mytomycin]] and diaziquone (AZQ). Cisplatin and derivatives include [[cisplatin]], [[carboplatin]] and [[oxaliplatin]].<ref name=lind /><ref name="pmid19002790">{{cite journal | vauthors = Damia G, D'Incalci M | title = Mechanisms of resistance to alkylating agents | journal = Cytotechnology | volume = 27 | issue = 1–3 | pages = 165–73 | date = September 1998 | pmid = 19002790 | pmc = 3449574 | doi = 10.1023/A:1008060720608 }}</ref> They impair cell function by forming [[covalent bond]]s with the [[amino group|amino]], [[carboxyl group|carboxyl]], [[sulfhydryl group|sulfhydryl]], and [[phosphate group]]s in biologically important molecules.<ref name=takimoto>{{cite book | vauthors = Takimoto CH, Calvo E | chapter-url = http://www.cancernetwork.com/cancer-management-11/chapter03/article/10165/1402628 | chapter = Principles of Oncologic Pharmacotherapy | veditors = Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ | title = Cancer Management: A Multidisciplinary Approach | edition = 11th | date = 2008 | access-date = 18 June 2009 | archive-date = 15 May 2009 | archive-url = https://web.archive.org/web/20090515221337/http://www.cancernetwork.com/cancer-management-11/chapter03/article/10165/1402628 | url-status = dead }}</ref> Non-classical alkylating agents include [[procarbazine]] and hexamethylmelamine.<ref name=lind /><ref name="pmid19002790" />

==== Antimetabolites ====
[[File:Deoxcytidine, Gemcitidine and Decitabine.png|thumb|[[Deoxycytidine]] (left) and two anti-metabolite drugs (center and right), [[gemcitabine]] and [[decitabine]]. The drugs are very similar but they have subtle differences in their [[chemical structure]].]]
{{Main|Antimetabolite}}
[[Anti-metabolite]]s are a group of molecules that impede DNA and RNA synthesis. Many of them have a similar structure to the building blocks of DNA and RNA. The building blocks are [[nucleotide]]s; a molecule comprising a [[nucleobase]], a sugar and a [[phosphate group]]. The nucleobases are divided into [[purine]]s ([[guanine]] and [[adenine]]) and [[pyrimidine]]s ([[cytosine]], [[thymine]] and [[uracil]]). Anti-metabolites resemble either nucleobases or nucleosides (a nucleotide without the phosphate group), but have altered [[chemical group]]s.<ref name="pmid19476376">{{cite journal | vauthors = Parker WB | title = Enzymology of purine and pyrimidine antimetabolites used in the treatment of cancer | journal = Chemical Reviews | volume = 109 | issue = 7 | pages = 2880–93 | date = July 2009 | pmid = 19476376 | pmc = 2827868 | doi = 10.1021/cr900028p }}</ref> These drugs exert their effect by either blocking the enzymes required for DNA synthesis or becoming incorporated into DNA or RNA. By inhibiting the enzymes involved in DNA synthesis, they prevent mitosis because the DNA cannot duplicate itself. Also, after misincorporation of the molecules into DNA, [[DNA damage]] can occur and programmed cell death ([[apoptosis]]) is induced. Unlike alkylating agents, anti-metabolites are cell cycle dependent. This means that they only work during a specific part of the cell cycle, in this case [[S-phase]] (the DNA synthesis phase). For this reason, at a certain dose, the effect plateaus and proportionally no more cell death occurs with increased doses. Subtypes of the anti-metabolites are the [[antifolate|anti-folates]], fluoropyrimidines, deoxynucleoside analogues and [[thiopurine]]s.<ref name=lind /><ref name="pmid19476376" />

The anti-folates include [[methotrexate]] and [[pemetrexed]]. Methotrexate inhibits [[dihydrofolate reductase]] (DHFR), an enzyme that regenerates [[tetrahydrofolate]] from [[dihydrofolate]]. When the enzyme is inhibited by methotrexate, the cellular levels of folate coenzymes diminish. These are required for [[thymidylate]] and purine production, which are both essential for DNA synthesis and cell division.<ref name=Airley2009/>{{rp|55–59}}<ref name=Wood2005/>{{rp|11}} Pemetrexed is another anti-metabolite that affects purine and pyrimidine production, and therefore also inhibits DNA synthesis. It primarily inhibits the enzyme [[thymidylate synthase]], but also has effects on DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase and [[glycinamide ribonucleotide formyltransferase]].<ref name="pmid15217974">{{cite journal | vauthors = Adjei AA | title = Pemetrexed (ALIMTA), a novel multitargeted antineoplastic agent | journal = Clinical Cancer Research | volume = 10 | issue = 12 Pt 2 | pages = 4276s–4280s | date = June 2004 | pmid = 15217974 | doi = 10.1158/1078-0432.CCR-040010 | s2cid = 31467685 }}</ref> The fluoropyrimidines include [[fluorouracil]] and [[capecitabine]]. Fluorouracil is a nucleobase analogue that is metabolised in cells to form at least two active products; 5-fluourouridine monophosphate (FUMP) and 5-fluoro-2'-deoxyuridine 5'-phosphate (fdUMP). FUMP becomes incorporated into RNA and fdUMP inhibits the enzyme thymidylate synthase; both of which lead to cell death.<ref name=Wood2005/>{{rp|11}} Capecitabine is a [[prodrug]] of 5-fluorouracil that is broken down in cells to produce the active drug.<ref name="pmid12515569">{{cite journal | vauthors = Wagstaff AJ, Ibbotson T, Goa KL | title = Capecitabine: a review of its pharmacology and therapeutic efficacy in the management of advanced breast cancer | journal = Drugs | volume = 63 | issue = 2 | pages = 217–36 | year = 2003 | pmid = 12515569 | doi = 10.2165/00003495-200363020-00009 }}</ref> The deoxynucleoside analogues include [[cytarabine]], [[gemcitabine]], [[decitabine]], [[azacitidine]], [[fludarabine]], [[nelarabine]], [[cladribine]], [[clofarabine]], and [[pentostatin]]. The thiopurines include [[thioguanine]] and [[mercaptopurine]].<ref name=lind /><ref name="pmid19476376" />

==== Anti-microtubule agents ====
[[File:Microtubules and alkaloids.png|thumb|left|''Vinca'' alkaloids prevent the assembly of microtubules, whereas taxanes prevent their disassembly. Both mechanisms cause defective mitosis.]]
[[Anti-microtubule agent]]s are [[plant]]-derived chemicals that block cell division by preventing [[microtubule]] function. Microtubules are an important cellular structure composed of two proteins, [[α-tubulin]] and [[β-tubulin]]. They are hollow, rod-shaped structures that are required for cell division, among other cellular functions.<ref name="pmid1687171">{{cite journal | vauthors = Rowinsky EK, Donehower RC | title = The clinical pharmacology and use of antimicrotubule agents in cancer chemotherapeutics | journal = Pharmacology & Therapeutics | volume = 52 | issue = 1 | pages = 35–84 | date = October 1991 | pmid = 1687171 | doi = 10.1016/0163-7258(91)90086-2 }}</ref> Microtubules are dynamic structures, which means that they are permanently in a state of assembly and disassembly. [[Vinca alkaloid|''Vinca'' alkaloids]] and [[taxane]]s are the two main groups of anti-microtubule agents, and although both of these groups of drugs cause microtubule dysfunction, their mechanisms of action are completely opposite: ''Vinca'' alkaloids prevent the assembly of microtubules, whereas taxanes prevent their disassembly. By doing so, they can induce [[mitotic catastrophe]] in the cancer cells.<ref>{{Cite journal |last1=Vitale |first1=Ilio |last2=Galluzzi |first2=Lorenzo |last3=Castedo |first3=Maria |last4=Kroemer |first4=Guido |date=June 2011 |title=Mitotic catastrophe: a mechanism for avoiding genomic instability |url=https://www.nature.com/articles/nrm3115 |journal=Nature Reviews Molecular Cell Biology |language=en |volume=12 |issue=6 |pages=385–392 |doi=10.1038/nrm3115 |pmid=21527953 |s2cid=22483746 |issn=1471-0072}}</ref>  Following this, cell cycle arrest occurs, which induces programmed cell death ([[apoptosis]]).<ref name=lind /><ref name="pmid20577942" /> These drugs can also affect [[Angiogenesis|blood vessel growth]], an essential process that tumours utilise in order to grow and metastasise.<ref name="pmid20577942">{{cite journal | vauthors = Yue QX, Liu X, Guo DA | title = Microtubule-binding natural products for cancer therapy | journal = Planta Medica | volume = 76 | issue = 11 | pages = 1037–43 | date = August 2010 | pmid = 20577942 | doi = 10.1055/s-0030-1250073 | doi-access = free | bibcode = 2010PlMed..76.1037Y }}</ref>

''Vinca'' alkaloids are derived from the [[Madagascar periwinkle]], ''Catharanthus roseus'',<ref>{{cite book|vauthors = Hirata K, Miyamoto K, Miura Y|chapter = ''Catharanthus roseus'' L. (Periwinkle): Production of Vindoline and Catharanthine in Multiple Shoot Cultures|title = Biotechnology in Agriculture and Forestry 26|series = Medicinal and Aromatic Plants|volume = VI|veditors = Bajaj YP|publisher = [[Springer-Verlag]]|year = 1994|pages = [https://archive.org/details/medicinalaromati0006unse/page/46 46–55]|chapter-url = https://books.google.com/books?id=e64hCDBddowC&pg=PA47|isbn = 9783540563914|url = https://archive.org/details/medicinalaromati0006unse/page/46}}</ref><ref>{{cite journal | vauthors = van Der Heijden R, Jacobs DI, Snoeijer W, Hallard D, Verpoorte R | title = The Catharanthus alkaloids: pharmacognosy and biotechnology | journal = Current Medicinal Chemistry | volume = 11 | issue = 5 | pages = 607–28 | date = March 2004 | pmid = 15032608 | doi = 10.2174/0929867043455846 }}</ref> formerly known as ''Vinca rosea''. They bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules. The original ''vinca'' alkaloids are [[natural product]]s that include [[vincristine]] and [[vinblastine]].<ref>{{cite book|title = Metal Catalyzed Reductive C—C Bond Formation: A Departure from Preformed Organometallic Reagents|volume = 279|series = Topics in Current Chemistry|pages = 25–52|year = 2007|chapter = Reductive C—C bond formation after epoxide opening via electron transfer| vauthors = Gansäuer A, Justicia J, Fan CA, Worgull D, Piestert F |doi = 10.1007/128_2007_130|chapter-url = https://books.google.com/books?id=A5xcVmT9iIQC&pg=PA25|editor-link1=Michael J. Krische|editor-first = Michael J.|editor-last = Krische|publisher = [[Springer Science & Business Media]]|isbn = 9783540728795}}</ref><ref>{{cite book|chapter = Africa's gift to the world|pages = 46–51|chapter-url = https://books.google.com/books?id=aXGmCwAAQBAJ&pg=PA46|title = Botanical Miracles: Chemistry of Plants That Changed the World|first1 = Raymond|last1 = Cooper|first2 = Jeffrey John|last2 = Deakin | name-list-style = vanc |publisher = [[CRC Press]]|year = 2016|isbn = 9781498704304}}</ref><ref name = MoleculesReview>{{cite journal | vauthors = Keglevich P, Hazai L, Kalaus G, Szántay C | title = Modifications on the basic skeletons of vinblastine and vincristine | journal = Molecules | volume = 17 | issue = 5 | pages = 5893–914 | date = May 2012 | pmid = 22609781 | pmc = 6268133 | doi = 10.3390/molecules17055893 | doi-access = free }}</ref><ref>{{cite book|last = Raviña|first = Enrique|title = The evolution of drug discovery: From traditional medicines to modern drugs|year = 2011|publisher = [[John Wiley & Sons]]|isbn = 9783527326693|pages = 157–159|chapter = Vinca alkaloids|chapter-url = https://books.google.com/books?id=iDNy0XxGqT8C&pg=PA157}}</ref> Following the success of these drugs, semi-synthetic ''vinca'' alkaloids were produced: [[vinorelbine]] (used in the treatment of [[non-small-cell lung cancer]]<ref name = MoleculesReview /><ref>{{cite journal | vauthors = Faller BA, Pandit TN | title = Safety and efficacy of vinorelbine in the treatment of non-small cell lung cancer | journal = Clinical Medicine Insights: Oncology | volume = 5 | pages = 131–44 | year = 2011 | pmid = 21695100 | pmc = 3117629 | doi = 10.4137/CMO.S5074 }}</ref><ref>{{cite journal | vauthors = Ngo QA, Roussi F, Cormier A, Thoret S, Knossow M, Guénard D, Guéritte F | title = Synthesis and biological evaluation of vinca alkaloids and phomopsin hybrids | journal = Journal of Medicinal Chemistry | volume = 52 | issue = 1 | pages = 134–42 | date = January 2009 | pmid = 19072542 | doi = 10.1021/jm801064y }}</ref>), [[vindesine]], and [[vinflunine]].<ref name="pmid20577942" /> These drugs are [[cell cycle]]-specific. They bind to the tubulin molecules in [[S-phase]] and prevent proper microtubule formation required for [[M-phase]].<ref name="pmid14508075" />

Taxanes are natural and semi-synthetic drugs. The first drug of their class, [[paclitaxel]], was originally extracted from ''[[Taxus brevifolia]]'', the Pacific yew. Now this drug and another in this class, [[docetaxel]], are produced semi-synthetically from a chemical found in the bark of another yew tree, ''[[Taxus baccata]]''.<ref>{{Cite journal |last1=Croteau |first1=Rodney |last2=Ketchum |first2=Raymond E. B. |last3=Long |first3=Robert M. |last4=Kaspera |first4=Rüdiger |last5=Wildung |first5=Mark R. |date=2006 |title=Taxol biosynthesis and molecular genetics |journal=Phytochemistry Reviews |volume=5 |issue=1 |pages=75–97 |doi=10.1007/s11101-005-3748-2 |issn=1568-7767 |pmc=2901146 |pmid=20622989|bibcode=2006PChRv...5...75C }}</ref>

[[Podophyllotoxin]] is an antineoplastic [[lignan]] obtained primarily from the [[Podophyllum|American mayapple]] (''Podophyllum peltatum'') and [[Sinopodophyllum|Himalayan mayapple]] (''Sinopodophyllum hexandrum''). It has anti-microtubule activity, and its mechanism is similar to that of ''vinca'' alkaloids in that they bind to tubulin, inhibiting microtubule formation. Podophyllotoxin is used to produce two other drugs with different mechanisms of action: [[etoposide]] and [[teniposide]].<ref name="pmid9562603">{{cite journal | vauthors = Damayanthi Y, Lown JW | title = Podophyllotoxins: current status and recent developments | journal = Current Medicinal Chemistry | volume = 5 | issue = 3 | pages = 205–52 | date = June 1998 | doi = 10.2174/0929867305666220314204426 | pmid = 9562603 | s2cid = 247493530 }}</ref><ref>{{cite journal |vauthors=Liu YQ, Yang L, Tian X |title=Podophyllotoxin: current perspectives |journal=Current Bioactive Compounds |year=2007 |volume=3 |issue=1 |pages=37–66 |doi=10.1016/j.jallcom.2006.06.070 }}</ref>

==== Topoisomerase inhibitors ====
[[File:Topoisomerase Inhibitor.JPG|thumb|Topoisomerase I and II Inhibitors]]
{{Main|Topoisomerase inhibitor}}
Topoisomerase inhibitors are drugs that affect the activity of two enzymes: [[topoisomerase I]] and [[topoisomerase II]]. When the DNA double-strand helix is unwound, during DNA replication or [[transcription (biology)|transcription]], for example, the adjacent unopened DNA winds tighter (supercoils), like opening the middle of a twisted rope. The stress caused by this effect is in part aided by the topoisomerase enzymes. They produce single- or double-strand breaks into DNA, reducing the tension in the DNA strand. This allows the normal unwinding of DNA to occur during [[DNA replication|replication]] or transcription. Inhibition of topoisomerase I or II interferes with both of these processes.<ref>{{cite book |vauthors=Lodish H, Berk A, Zipursky SL |title=Molecular Cell Biology. 4th edition. The Role of Topoisomerases in DNA Replication|year=2000|publisher=New York: W. H. Freeman|url=https://www.ncbi.nlm.nih.gov/books/NBK21703/|display-authors=etal }}</ref><ref name="pmid12351817">{{cite journal | vauthors = Goodsell DS | title = The molecular perspective: DNA topoisomerases | journal = Stem Cells | volume = 20 | issue = 5 | pages = 470–1 | year = 2002 | pmid = 12351817 | doi = 10.1634/stemcells.20-5-470 | s2cid = 9257158 | doi-access = free }}</ref>

Two topoisomerase I inhibitors, [[irinotecan]] and [[topotecan]], are semi-synthetically derived from [[camptothecin]], which is obtained from the Chinese ornamental tree ''[[Camptotheca acuminata]]''.<ref name="pmid14508075" /> Drugs that target topoisomerase II can be divided into two groups. The topoisomerase II poisons cause increased levels enzymes bound to DNA. This prevents DNA replication and transcription, causes DNA strand breaks, and leads to programmed cell death ([[apoptosis]]). These agents include [[etoposide]], [[doxorubicin]], [[mitoxantrone]] and [[teniposide]]. The second group, catalytic inhibitors, are drugs that block the activity of topoisomerase II, and therefore prevent DNA synthesis and translation because the DNA cannot unwind properly. This group includes [[novobiocin]], merbarone, and [[aclarubicin]], which also have other significant mechanisms of action.<ref name="pmid19377506">{{cite journal | vauthors = Nitiss JL | title = Targeting DNA topoisomerase II in cancer chemotherapy | journal = Nature Reviews. Cancer | volume = 9 | issue = 5 | pages = 338–50 | date = May 2009 | pmid = 19377506 | pmc = 2748742 | doi = 10.1038/nrc2607 }}</ref>

==== Cytotoxic antibiotics ====
The cytotoxic [[antibiotic]]s are a varied group of drugs that have various mechanisms of action. The common theme that they share in their chemotherapy indication is that they interrupt [[cell division]]. The most important subgroup is the [[anthracycline]]s and the [[bleomycin]]s; other prominent examples include [[mitomycin C]] and [[actinomycin]].<ref name = "Offermanns_2008">{{cite book |url=https://books.google.com/books?id=iwwo5gx8aX8C&pg=PA155 |title=Encyclopedia of Molecular Pharmacology | vauthors = Offermanns S, Rosenthal W |date=2008-08-14 |publisher=Springer Science & Business Media |isbn=9783540389163 | page = 155 }}</ref>

Among the anthracyclines, [[doxorubicin]] and [[daunorubicin]] were the first, and were obtained from the [[bacterium]] ''[[Streptomyces peucetius]]''.<ref>{{Cite book |url=https://books.google.com/books?id=iwwo5gx8aX8C&pg=PA91 |title=Encyclopedia of Molecular Pharmacology | vauthors = Offermanns S, Rosenthal W  |date=2008-08-14 |publisher=Springer Science & Business Media |isbn=9783540389163 |pages=91ff }}</ref> Derivatives of these compounds include [[epirubicin]] and [[idarubicin]]. Other clinically used drugs in the anthracycline group are [[pirarubicin]], [[aclarubicin]], and [[mitoxantrone]].<ref>{{cite journal | pmid = 3048848| year = 1988| vauthors = Koeller J, Eble M | title = Mitoxantrone: A novel anthracycline derivative| journal = Clinical Pharmacy| volume = 7| issue = 8| pages = 574–81 }}</ref> The mechanisms of anthracyclines include [[DNA intercalation]] (molecules insert between the two strands of DNA), generation of highly reactive [[free radicals]] that damage intercellular molecules and topoisomerase inhibition.<ref name="pmid15169927">{{cite journal | vauthors = Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L | s2cid = 13138853 | title = Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity | journal = Pharmacological Reviews | volume = 56 | issue = 2 | pages = 185–229 | date = June 2004 | pmid = 15169927 | doi = 10.1124/pr.56.2.6 }}</ref>

Actinomycin is a complex molecule that intercalates DNA and prevents [[RNA synthesis]].<ref name="pmid2410919">{{cite journal | vauthors = Sobell HM | title = Actinomycin and DNA transcription | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 82 | issue = 16 | pages = 5328–31 | date = August 1985 | pmid = 2410919 | pmc = 390561 | doi = 10.1073/pnas.82.16.5328 | bibcode = 1985PNAS...82.5328S | doi-access = free }}</ref>

Bleomycin, a [[glycopeptide]] isolated from ''[[Streptomyces verticillus]]'', also intercalates DNA, but produces [[free radical]]s that damage DNA. This occurs when bleomycin binds to a [[metal ion]], becomes [[reduction (chemistry)|chemically reduced]] and reacts with [[oxygen]].<ref name="pmid1384141">{{cite journal | vauthors = Dorr RT | title = Bleomycin pharmacology: mechanism of action and resistance, and clinical pharmacokinetics | journal = Seminars in Oncology | volume = 19 | issue = 2 Suppl 5 | pages = 3–8 | date = April 1992 | pmid = 1384141 }}</ref><ref name=Airley2009/>{{rp|87}}

Mitomycin is a cytotoxic antibiotic with the ability to alkylate DNA.<ref name="pmid2131038">{{cite journal | vauthors = Verweij J, Pinedo HM | title = Mitomycin C: mechanism of action, usefulness and limitations | journal = Anti-Cancer Drugs | volume = 1 | issue = 1 | pages = 5–13 | date = October 1990 | pmid = 2131038 | doi = 10.1097/00001813-199010000-00002 }}</ref>

=== Delivery ===
[[File:Pediatric patients receiving chemotherapy.jpg|thumb|Two girls with [[acute lymphoblastic leukemia]] receiving chemotherapy. The girl on the left has a [[central venous catheter]] inserted in her neck. The girl on the right has a [[peripheral venous catheter]]. The arm board stabilizes the arm during needle insertion. Anti-cancer IV drip is seen at top right.]]
Most chemotherapy is [[Route of administration|delivered]] [[intravenous therapy|intravenously]], although a number of agents can be administered orally (e.g., [[melphalan]], [[busulfan]], [[capecitabine]]). According to a recent (2016) systematic review, oral therapies present additional challenges for patients and care teams to maintain and support adherence to treatment plans.<ref>{{cite journal | vauthors = Greer JA, Amoyal N, Nisotel L, Fishbein JN, MacDonald J, Stagl J, Lennes I, Temel JS, Safren SA, Pirl WF | display-authors = 6 | title = A Systematic Review of Adherence to Oral Antineoplastic Therapies | journal = The Oncologist | volume = 21 | issue = 3 | pages = 354–76 | date = March 2016 | pmid = 26921292 | pmc = 4786357 | doi = 10.1634/theoncologist.2015-0405 }}</ref>

There are many intravenous methods of drug delivery, known as vascular access devices. These include the [[Winged infusion set|winged infusion device]], [[peripheral venous catheter]], midline catheter, [[peripherally inserted central catheter]] (PICC), [[central venous catheter]] and [[implantable port]]. The devices have different applications regarding duration of chemotherapy treatment, method of delivery and types of chemotherapeutic agent.<ref name=Wood2005/>{{rp|94–95}}

Depending on the person, the cancer, the stage of cancer, the type of chemotherapy, and the dosage, intravenous chemotherapy may be given on either an [[inpatient]] or an [[outpatient]] basis. For continuous, frequent or prolonged intravenous chemotherapy administration, various systems may be surgically inserted into the vasculature to maintain access.<ref name=Wood2005/>{{rp|113–118}} Commonly used systems are the [[Hickman line]], the [[Port-a-Cath]], and the [[PICC line]]. These have a lower infection risk, are much less prone to [[phlebitis]] or [[extravasation]], and eliminate the need for repeated insertion of peripheral cannulae.<ref>{{Cite journal |last1=O'Grady |first1=Naomi P. |last2=Alexander |first2=Mary |last3=Burns |first3=Lillian A. |last4=Dellinger |first4=E. Patchen |last5=Garland |first5=Jeffrey |last6=Heard |first6=Stephen O. |last7=Lipsett |first7=Pamela A. |last8=Masur |first8=Henry |last9=Mermel |first9=Leonard A. |last10=Pearson |first10=Michele L. |last11=Raad |first11=Issam I. |last12=Randolph |first12=Adrienne G. |last13=Rupp |first13=Mark E. |last14=Saint |first14=Sanjay |date=2011-05-01 |title=Guidelines for the Prevention of Intravascular Catheter-related Infections |journal=Clinical Infectious Diseases|volume=52 |issue=9 |pages=e162–e193 |doi=10.1093/cid/cir257 |issn=1058-4838 |pmc=3106269 |pmid=21460264}}</ref>

[[Isolated limb perfusion]] (often used in [[melanoma]]),<ref name="pmid20348274">{{cite journal | vauthors = Moreno-Ramirez D, de la Cruz-Merino L, Ferrandiz L, Villegas-Portero R, Nieto-Garcia A | title = Isolated limb perfusion for malignant melanoma: systematic review on effectiveness and safety | journal = The Oncologist | volume = 15 | issue = 4 | pages = 416–27 | year = 2010 | pmid = 20348274 | pmc = 3227960 | doi = 10.1634/theoncologist.2009-0325 }}</ref> or isolated infusion of chemotherapy into the liver<ref name="pmid18722924">{{cite journal | vauthors = Verhoef C, de Wilt JH, ten Hagen TL, Eggermont AM | title = Isolated hepatic perfusion for the treatment of liver tumors: sunset or sunrise? | journal = Surgical Oncology Clinics of North America | volume = 17 | issue = 4 | pages = 877–94, xi | date = October 2008 | pmid = 18722924 | doi = 10.1016/j.soc.2008.04.007 }}</ref> or the lung have been used to treat some tumors. The main purpose of these approaches is to deliver a very high dose of chemotherapy to tumor sites without causing overwhelming systemic damage.<ref name="pmid10421507">{{cite journal | vauthors = Hendriks JM, Van Schil PE | title = Isolated lung perfusion for the treatment of pulmonary metastases | journal = Surgical Oncology | volume = 7 | issue = 1–2 | pages = 59–63 | year = 1998 | pmid = 10421507 | doi = 10.1016/S0960-7404(98)00028-0 }}</ref> These approaches can help control solitary or limited metastases, but they are by definition not systemic, and, therefore, do not treat distributed metastases or [[micrometastasis|micrometastases]].{{citation needed|date=December 2021}}

Topical chemotherapies, such as [[5-fluorouracil]], are used to treat some cases of [[non-melanoma skin cancer]].<ref>{{cite journal | vauthors = Chitwood K, Etzkorn J, Cohen G | title = Topical and intralesional treatment of nonmelanoma skin cancer: efficacy and cost comparisons | journal = Dermatologic Surgery | volume = 39 | issue = 9 | pages = 1306–16 | date = September 2013 | pmid = 23915332 | doi = 10.1111/dsu.12300 | s2cid = 597295 }}</ref>

If the cancer has [[central nervous system]] involvement, or with meningeal disease, [[intrathecal]] chemotherapy may be administered.<ref name=Corrie />